The present invention relates to compounds which elevate pyruvate dehydrogenase (PDH) activity, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states associated with reduced PDH activity, to their use as medicaments and to their use in the manufacture of medicaments for use in the elevation of PDH activity in warm-blooded animals such as humans.
Within tissues adenosine triphosphate (ATP) provides the energy for synthesis of complex molecules and, in muscle, for contraction. ATP is generated from the breakdown of energy-rich substrates such as glucose or long chain free fatty acids. In oxidative tissues such as muscle the majority of the ATP is generated from acetyl CoA which enters the citric acid cycle, thus the supply of acetyl CoA is a critical determinant of ATP production in oxidative tissues. Acetyl CoA is produced either by xcex2-oxidation of fatty acids or as a result of glucose metabolism by the glycolytic pathway. The key regulatory enzyme in controlling the rate of acetyl CoA formation from glucose is PDH which catalyses the oxidation of pyruvate to acetyl CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.
In disease states such as both non-insulin dependent (NIDDM) and insulin-dependent diabetes mellitus (IDDM), oxidation of lipids is increased with a concomitant reduction in utilisation of glucose, which contributes to the hyperglycaemia. Reduced glucose utilisation in both IDDM and NIDDM is associated with a reduction in PDH activity. In addition, a further consequence of reduced PDH activity may be that an increase in pyruvate concentration results in increased availability of lactate as a substrate for hepatic gluconeogenesis. It is reasonable to expect that increasing the activity of PDH could increase the rate of glucose oxidation and hence overall glucose utilisation, in addition to reducing hepatic glucose output. Another factor contributing to diabetes mellitus is impaired insulin secretion, which has been shown to be associated with reduced PDH activity in pancreatic xcex2-cells (in a rodent genetic model of diabetes mellitus Zhou et al. (1996) Diabetes 45: 580-586).
Oxidation of glucose is capable of yielding more molecules of ATP per mole of oxygen than is oxidation of fatty acids. In conditions where energy demand may exceed energy supply, such as myocardial ischaemia, intermittent claudication, cerebral ischaemia and reperfusion, (Zaidan et al., 1998; J. Neurochem. 70: 233-241), shifting the balance of substrate utilisation in favour of glucose metabolism by elevating PDH activity may be expected to improve the ability to maintain ATP levels and hence function.
An agent which is capable of elevating PDH activity may also be expected to be of benefit in treating conditions where an excess of circulating lactic acid is manifest such as in certain cases of sepsis.
The agent dichloroacetic acid (DCA) which increases the activity of PDH after acute administration in animals, (Vary et al., 1988; Circ. Shock, 24: 3-18), has been shown to have the predicted effects in reducing glycaemia, (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530), and as a therapy for myocardial ischaemia (Bersin and Stacpoole 1997; American Heart Journal, 134: 841-855) and lactic acidaemia, (Stacpoole et al., 1983; N. Engl. J. Med. 309: 390-396).
PDH is an intramitochondrial multienzyme complex consisting of multiple copies of several subunits including three enzyme activities E1, E2 and E3, required for the completion of the conversion of pyruvate to acetyl CoA (Patel and Roche 1990; FASEB J., 4: 3224-3233). E1 catalyses the non-reversible removal of CO2 from pyruvate; E2 forms acetyl CoA and E3 reduces NAD to NADH. Two additional enzyme activities are associated with the complex: a specific kinase which is capable of phosphorylating E1 at three serine residues and a loosely-associated specific phosphatase which reverses the phosphorylation. Phosphorylation of a single one of the three serine residues renders the E1 inactive. The proportion of the PDH in its active (dephosphorylated) state is determined by a balance between the activity of the kinase and phosphatase. The activity of the kinase may be regulated in vivo by the relative concentrations of metabolic substrates such as NAD/NADH, CoA/acetylCoA and adenine diphosphate (ADP)/ATP as well as by the availability of pyruvate itself.
European Patent Publication No. 625516 refers to compounds which are capable of relaxing bladder smooth muscle and which may be used in the treatment of urge incontinence. We have found, surprisingly, that compounds also containing a sulphonamide moiety disclosed in the present invention are very good at elevating PDH activity, a property nowhere disclosed in EP 625516.The present invention is based on the surprising discovery that certain compounds elevate PDH activity, a property of value in the treatment of disease states associated with disorders of glucose utilisation such as diabetes mellitus, obesity, (Curto et al., 1997; Int. J. Obes. 21: 1137-1142), and lactic acidaemia. Additionally the compounds may be expected to have utility in diseases where supply of energy-rich substrates to tissues is limiting such as peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, muscle weakness, hyperlipidaemias and atherosclerosis (Stacpoole et al., 1978; N. Engl. J. Med. 298: 526-530). A compound that activates PDH may also be useful in treating Alzheimer disease (AD) (J Neural Transm (1998) 105: 855-870).
Accordingly, the present invention provides a compound of formula (I): 
wherein:
Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide;
R1 and R2 are independently as defined in (a) or (b);
R3 and R4 are as defined in (c) or (d);
R5 is as defined in (e) or (f);
Yxe2x80x94Z is as defined in (g) or (h)
wherein:
(a) either R1 and R2 are each selected independently from hydrogen, C1-3alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents selected independently from C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano,
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl;
(b) either R1 and R2 are each selected independently from phenyl substituted by one or more P (wherein P is as defined hereinbelow), phenyl substituted by one or more groups selected from C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano and additionally substituted by one or more groups selected from P, a heterocyclic group other than unsubstituted pyridyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), naphthyl optionally substituted by one or more Q, C4-6alkyl, C3-6cycloalkyl optionally substituted with one or more Q, C2-6alkenyl, C2-6alkynyl, C1-6alkyl substituted by one or more V (wherein V is as defined hereinbelow), R6T- (wherein R6 and T are as defined hereinbelow) and R7C1-6alkylT- (where R7 is as defined hereinbelow),
or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group other than unsubstituted morpholino, unsubstituted thiomorpholino, unsubstituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted imidazolyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);
(c) either R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3, provided that R3 and R4 are not both methyl;
or R3 and R4 together with the carbon atom to which they are attached, form a Cmcycloalkyl ring optionally substituted by from 1 to 2m-2 fluorine atoms wherein m is 3-5;
(d) R3 and R4 are both methyl;
(e) R5 is hydrogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, C2-4alkenyloxy or trifluoromethylthio;
(f) R5 is halo, hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphanoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, formyl, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, C5-6alkyl, haloC5-6alkyl, C5-6alkoxy, haloC5-6alkoxy or C5-6alkenyloxy;
(g) Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, trans-vinylene, and ethynylene;
(h) Yxe2x80x94Z is xe2x80x94NHC(S)xe2x80x94;
R1 is selected from C1-6alkyl (optionally substituted with one or more R8), C3-6cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R7 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R8 is trifluoromethyl, C1-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, C1-6alkoxy, formyl, C1-6alkanoyl, C1-6alkanoyloxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, nitro, carboxy, carbamoyl, C1-6alkoxycarbonyl, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphanoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl aminosulphonyl carbamoylC1-6alkyl, N-(C1-6alkyl)carbamoylC1-6alkyl, N-(C1-6alalkyl, hydroxy-C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, phenylC1-6alkyl or phenylC1-6alkoxy;
P is selected from xe2x80x94C2-6alkyl-Mxe2x80x94 substituted with one or more R9, xe2x80x94C2-6alkenyl-Mxe2x80x94 optionally substituted with one or more R9, xe2x80x94C2-6alkynyl-Mxe2x80x94 optionally substituted with one or more R9 (with the proviso that in the three previous groups R9 is not a substituent on the carbon atom attached to M), R10xe2x80x94CH2xe2x80x94Mxe2x80x94, R11xe2x80x94Mxe2x80x94, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, nitro, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, formyl, C1-6alkanoyl, C5-6alkyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkanoylaminosulphonyl, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)aminosulphonyl, C1-6alkylsulpbonylaminocarbonyl, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)aminocarbonyl, C5-6alkoxy, C5-6alkenyloxy, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 and a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);
Q is selected from any of the values defined for P, C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano;
V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, a heterocyclic group optionally substituted on a ring carbon by one or more Q and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow) or C3-6cycloalkyl optionally substituted with one or more Q;
T is selected from xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94C(O)N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94N(Nxe2x80x94C1-6alkyl)C(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94NHC(S)xe2x80x94, xe2x80x94C(S)N(Nxe2x80x94C1-6alkyl)xe2x80x94 and xe2x80x94N(Nxe2x80x94C1-6alkyl)C(S)xe2x80x94;
M is selected from xe2x80x94Oxe2x80x94, xe2x80x94N(R12)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94C(O)N(R12)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94N(R12)C(O)Oxe2x80x94, xe2x80x94OC(O)N(R12)xe2x80x94, xe2x80x94C(S)N(R12)xe2x80x94, xe2x80x94N(R12)C(S)xe2x80x94, xe2x80x94SO2N(R12)xe2x80x94, xe2x80x94N(R12)SO2xe2x80x94 and xe2x80x94N(R12)C(O)N(R12)xe2x80x94, xe2x80x94N(R12)C(S)N(R12)xe2x80x94, xe2x80x94SO2NHC(O)xe2x80x94, xe2x80x94SO2N(R12)C(O)xe2x80x94, xe2x80x94C(O)NHSO2xe2x80x94, xe2x80x94C(O)N(R12)SO2xe2x80x94 or M is a direct bond;
D is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzoyl, (heterocyclic group)carbonyl, phenylsulphonyl, (heterocyclic group)sulphonyl, phenyl or a carbon linked heterocyclic group, and wherein any C1-6alkyl group may be optionally substituted by one or more R9, and wherein any phenyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R8 and if a heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from E;
E is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkanoyl, phenylC1-6alkyl, benzoyl, phenylC1-6alkanoyl, phenylC1-6alkoxycarbonyl and phenylsulphonyl.
R9 is selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, formyl, sulphamoyl, Nxe2x80x94C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylamino, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl;
R10 is carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8;
R11 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8, C3-6cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8;
R12 is hydrogen or C1-6alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon attached to the nitrogen atom of M;
R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, C1-6alkanoyl or formyl;
n is 0-2;
with the proviso that where R1 and R2 are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and Ring X is phenyl, Yxe2x80x94Z must be xe2x80x94NHC(S)xe2x80x94;
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, and with the proviso that when R3 and R4 are both methyl, R5 is hydrogen, fluoro or chloro, Yxe2x80x94Z is ethynylene, X is phenyl and one of R1 and R2 is hydrogen and the other is pyrimidyl-NHxe2x80x94C(O)xe2x80x94 or triazinyl-NHxe2x80x94C(O)xe2x80x94 (wherein said triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) then the xe2x80x94SO2NR1R2 moiety cannot be ortho to Yxe2x80x94Z; and provided said compound is not:
4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide,
N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, or
N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.
In this specification the term xe2x80x9calkylxe2x80x9d includes both straight and branched chain alkyl groups but references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. For example, xe2x80x9cC1-4alkylxe2x80x9d includes propyl, isopropyl and t-butyl. However, references to individual alkyl groups such as xe2x80x98propylxe2x80x99 are specific for the straight chained version only and references to individual branched chain alkyl groups such as xe2x80x98isopropylxe2x80x99 are specific for the branched chain version only. A similar convention applies to other radicals, for example xe2x80x9chaloC1-4alkylxe2x80x9d includes 1-chloroethyl and 2-fluoroethyl. The term xe2x80x9chaloxe2x80x9d refers to fluoro, chloro, bromo and iodo. Where a phrase such as xe2x80x9cany C1-6alkyl group may be optionally substituted by one or more groupsxe2x80x9d for the avoidance of doubt, it is to be understood that this refers to all groups that contains a C1-6alkyl group, for example this phrase would also relate to a C1-6alkanoyl group if that was listed in the paragraph.
A xe2x80x9cheterocyclic groupxe2x80x9d is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94C(O)xe2x80x94, a ring nitrogen atom may optionally bear a C1-6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Examples and suitable values of the term xe2x80x9cheterocyclic groupxe2x80x9d are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, N-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
A xe2x80x9csix membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxidexe2x80x9d is an unsaturated monocyclic ring containing six atoms. Examples are pyridine, pyrimidine, pyrazine and pyridine-N-oxide.
Suitable values when R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group are morpholino, piperidyl, piperazinyl, indolinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, indolyl, isoindolyl and benzimidazolyl. Especially morpholino, piperidyl, piperazinyl, indolinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl and homopiperazinyl.
An example of xe2x80x9cC1-6alkanoyloxyxe2x80x9d is acetoxy. Examples of xe2x80x9cC1-6alkoxycarbonylxe2x80x9d include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of xe2x80x9cC1-6alkoxyxe2x80x9d include methoxy, ethoxy and propoxy. Examples of xe2x80x9cC1-6alkanoylaminoxe2x80x9d include formamido, acetamido and propionylamino. Examples of xe2x80x9cC1-4alkylsulphanylxe2x80x9d include methylthio and ethylthio. Examples of xe2x80x9cC1-4alkylsulphinylxe2x80x9d include methylsulphinyl and ethylsulphinyl. Examples of xe2x80x9cC1-4alkylsulphonylxe2x80x9d include mesyl and ethylsulphonyl. Examples of xe2x80x9cC1-6alkanoylxe2x80x9d include propionyl and acetyl. Examples of xe2x80x9cC1-6alkylaminoxe2x80x9d include methylamino and ethylamino. Examples of xe2x80x9c(C1-6alkyl)2aminoxe2x80x9d include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of xe2x80x9cC1-6alkoxyC1-6alkylxe2x80x9d methoxymethyl and propoxyethyl. Examples of xe2x80x9ccarbanoylC1-6alkylxe2x80x9d are carbamoylmethyl and 2-carbanoylethyl. Examples of xe2x80x9cN-(C1-6alkyl)carbamoylC1-6alkylxe2x80x9d are N-(methyl)aminocarbonylethyl and N-(ethyl)aminocarbonylpropyl. Examples of xe2x80x9cN-(C1-6alkyl)2carbamoylC1-6alkylxe2x80x9d are N,N-(dimethyl)aminocarbonylethyl and N-(methyl)N-(ethyl)aminocarbonylpropyl. Examples of xe2x80x9cC2-4alkenyloxyxe2x80x9d are vinyloxy and allyloxy. Examples of xe2x80x9cC3-6cycloalkylxe2x80x9d are cyclopropyl and cyclohexyl. Examples of xe2x80x9cC2-6alkenylxe2x80x9d are vinyl, allyl and 1-propenyl. Examples of xe2x80x9cC2-6alkynylxe2x80x9d are ethynyl, 1-propynyl and 2-propynyl. Examples of xe2x80x9chaloC1-4alkoxyxe2x80x9d are 2-fluoroethoxy and 1-bromopropoxy. Examples of xe2x80x9cC1-6alkanoyl(Nxe2x80x94C1-6alkyl)aminoxe2x80x9d are (N-methyl)formamido and (N-propyl)acetamido. Examples of xe2x80x9cC1-6alkylsulphonylaminoxe2x80x9d are methylsulphonylamino and ethylsulphonylamino. Examples of xe2x80x9cC1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)aminoxe2x80x9d are methylsulphonyl-(N-ethyl)-amino and ethylsulphonyl-(N-butyl)-amino. Examples of xe2x80x9cN-(C1-6alkyl)aminosulphonylxe2x80x9d are N-(methyl)aminosulphonyl and N-(ethyl)aminosulphonyl. Examples of xe2x80x9cN-(C1-6alkyl)2aminosulphonylxe2x80x9d are N,N-(dimethyl)aminosulphonyl and N-(methyl)-N-(ethyl)aminosulphonyl. Examples of xe2x80x9cN-(C1-6alkyl)carbamoylxe2x80x9d are methylaminocarbonyl and ethylaminocarbonyl. Examples of xe2x80x9cNxe2x80x94(C1-6alkyl)2carbamoylxe2x80x9d are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of xe2x80x9cphenylC1-6alkylxe2x80x9d are benzyl and phenethyl. Examples of xe2x80x9cphenylC1-6alkoxyxe2x80x9d are benzyloxy and phenylethoxy. Examples of xe2x80x9cC1-6alkanoylaminosulphonylxe2x80x9d are acetylaminosulphonyl and propionylaminosulphonyl. Examples of xe2x80x9cC1-6alkanoyl(Nxe2x80x94C1-6alkyl)aminosulphonylxe2x80x9d are acetyl(N-methyl)aminosulphonyl and propionyl(N-ethyl)aminosulphonyl. Examples of xe2x80x9cC1-6alkylsulphonylaminocarbonylxe2x80x9d are mesylaminocarbonyl and ethanesulphonylaminocarbonyl. Examples of xe2x80x9cC1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)aminocarbonylxe2x80x9d are N-(methyl)mesylaminocarbonyl and N-(methyl)ethanesulphonylaminocarbonyl. Examples of xe2x80x9cC1-6alkoxyC1-6alkanoylxe2x80x9d are methyoxyacetyl and ethoxypropionyl. Examples of xe2x80x9cphenylC1-6alkanoylxe2x80x9d are phenylacetyl and phenylpropionyl. Examples of xe2x80x9c(heterocyclic group)carbonylxe2x80x9d are pyrid-3-ylcarbonyl and pyrimid-2-ylcarbonyl. Examples of xe2x80x9c(heterocyclic group)C1-6alkanoylxe2x80x9d are pyrid-3-ylacetyl and pyrimid-2-ylpropionyl. Examples of xe2x80x9cphenylC1-6alkoxycarbonylxe2x80x9d are benzyloxycarbonyl and phenethyloxycarbonyl.
Another aspect of the invention provides a compound of formula (I) as depicted above wherein:
Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide;
R1 and R2 are independently as defined in (a) or (b);
R3 and R4 are as defined in (c) or (d);
R5 is as defined in (e) or (f);
Yxe2x80x94Z is as defined in (g) or (h)
wherein:
(a) either R1 and R2 are each selected independently from hydrogen, C1-3alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents selected independently from C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano,
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl;
(b) either R1 and R2 are each selected independently from phenyl substituted by one or more P (wherein P is as defined hereinbelow), a heterocyclic group other than unsubstituted pyridyl which is optionally substituted by one or more Q (wherein Q is as defined hereinbelow), naphthyl optionally substituted by one or more Q, C4-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl substituted by one or more V (wherein V is as defined hereinbelow), R6T-(wherein R6 and T are as defined hereinbelow) and R7C1-6alkylT- (where R7 is as defined hereinbelow),
or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group other than morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl;
(c) either R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3, provided that R3 and R4 are not both methyl;
or R3 and R4 together with the carbon atom to which they are attached, form a Cm cycloalkyl ring optionally substituted by from 1 to 2mxe2x88x922 fluorine atoms wherein m is 3-5;
(d) R3 and R4 are both methyl;
(e) R5 is hydrogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, C2-4alkenyloxy or trifluoromethylthio;
(f) R5 is halo, hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkylsulphonamido, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)amino thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkyloxycarbonyl, C1-6akanoyl, C2-6alkenyl, C2-6alkynyl, C5-6alkyl, haloC5-6alkyl, C5-6alkoxy, haloC5-6alkoxy or C5-6alkenyloxy;
(g) Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, trans-vinylene, and ethynylene;
(h) Yxe2x80x94Z is xe2x80x94NHC(S)xe2x80x94;
R6 is selected from C1-6alkyl, C3-6cycloalkyl, a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R1 is a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R1 is trifluoromethyl, C1-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, C1-6alkoxy, C1-6alkanoyl, C1-6alkanoyloxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, nitro, carboxy, carbamoyl, C1-6alkoxycarbonyl, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carbamoylC1-6alkyl, N-(C1-6alkyl)carbamoylC1-6alkyl, N-(C1-6alkyl)2carbamoyl-C1-6alkyl, hydroxyC1-6alkyl or C1-6alkoxyC1-6alkyl;
P is selected from R9xe2x80x94C2-6alkyl-Mxe2x80x94, R9xe2x80x94C2-6alkenylxe2x80x94Mxe2x80x94, R9xe2x80x94C2 alkynyl-Mxe2x80x94, R10xe2x80x94CH2xe2x80x94Mxe2x80x94, R11xe2x80x94Mxe2x80x94, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, nitro, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, C1-6alkanoyl, C5-6alkyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C5-6alkyl, C5-6alkenyloxy, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, and a heterocyclic group optionally substituted by one or more R8;
Q is selected from any of the values defined for P, C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano;
V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q or a heterocyclic group optionally substituted by one or more Q;
T is selected from xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94C(S)N(Nxe2x80x94C1-6alkyl)xe2x80x94;
M is selected from O, xe2x80x94N(R12)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94C(O)N(R12)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94N(R12)C(O)Oxe2x80x94, xe2x80x94OC(O)N(R12)xe2x80x94, xe2x80x94C(S)N(R12)xe2x80x94, xe2x80x94N(R12)C(S)xe2x80x94, xe2x80x94SO2N(R12)xe2x80x94, xe2x80x94N(R12)SO2xe2x80x94 and xe2x80x94N(R12)C(O)N(R12)xe2x80x94, xe2x80x94N(R12)C(S)N(R12)xe2x80x94, xe2x80x94SO2NHC(O)xe2x80x94, xe2x80x94C(O)NHSO2xe2x80x94 or M is a direct bond;
R9 is selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, Nxe2x80x94C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl;
R10 is carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonyl, a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8;
R11 is a heterocyclic group optionally substituted by one or more R8, phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8;
R12 is hydrogen or C1-6alkyl;
n is 0-2;
with the proviso that where R1 and R2 are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and Ring X is phenyl, Yxe2x80x94Z must be xe2x80x94NHC(S)xe2x80x94;
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, provided said compound is not
4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide;
N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide, or
N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.
A further aspect of the invention provides a compound of formula (I) as depicted above wherein:
Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide;
either R1 and R2 are each selected independently from hydrogen, C1-6alkyl, phenyl optionally substituted by one or more P, a heterocyclic group optionally substituted on a ring carbon by one or more P and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, naphthyl optionally substituted by one or more P, C3-6cycloalkyl optionally substituted with one or more P, C2-6alkenyl, C2-6alkynyl, C1-6alkyl substituted by one or more V, R6T- and R7C1-6alkylT-,
or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group optionally substituted on a ring carbon by one or more P and wherein if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D;
either R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3,
or R3 and R4 together with the carbon atom to which they are attached, form a Cmcycloalkyl ring optionally substituted by from 1 to 2mxe2x88x922 fluorine atoms wherein m is 3-5;
R5 is halo, hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoylsulphonamido, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkoxyalkyloxycarbonyl, formyl, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, C5-6alkyl, haloC5-6alkyl, C5-6alkoxy, haloC5-6alkoxy or C5-6alkenyloxy;
Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHC(S)xe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94, xe2x80x94NHCH2xe2x80x94, trans-vinylene, and ethynylene;
R6 is selected from C1-6alkyl (optionally substituted with one or more R8), C3-6cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R7 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R8 is trifluoromethyl, C1-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, C1-6alkoxy, formyl, C1-6alkanoyl, C1-6alkanoyloxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoyl amino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, nitro, carboxy, carbamoyl, C1-6alkoxycarbonyl, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carbamoylC1-6alkyl, N-(C1-6alkyl)carbamoylC1-6alkyl, N-(C1-6alkyl)2carbamoyl-C, alkyl, hydroxyC1-6alkyl, C1-6alkoxyC1-6alkyl, phenylC1-6alkyl or phenylC1-6alkoxy;
P is selected from C2-6alkyl-Mxe2x80x94 substituted with one or more R9, C2-6alkenyl-Mxe2x80x94 optionally substituted with one or more R9, C2-6alkynyl-Mxe2x80x94 optionally substituted with one or more R9 (with the proviso that in the three previous groups R9 is not a substituent on the carbon atom attached to M), R1xe2x88x92xe2x80x94CH2xe2x80x94Mxe2x80x94, R11xe2x80x94Mxe2x80x94, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, nitro, carboxy, hydroxy, halo, cyano C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, formyl, C1-6alkanoyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkanoylaminosulphonyl, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)aminosulphonyl, C1-6alkylsulphonylaminocarbonyl, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)aminocarbonyl, C1-6alkoxy, C2-6alkenyloxy, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 and a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D;
V is selected from any of the values defined for P, phenyl optionally substituted by one or more P, naphthyl optionally substituted by one or more P, a heterocyclic group optionally substituted on a ring carbon by one or more P and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D or C3-6cycloalkyl optionally substituted with one or more P;
T is selected from xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94C(O)N(Nxe2x80x94C1-6alkyl)xe2x80x94, xe2x80x94N(Nxe2x80x94C1-6alkyl)C(O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94NHC(S)xe2x80x94, xe2x80x94C(S)N(Nxe2x80x94C1-6alkyl)xe2x80x94 and xe2x80x94N(Nxe2x80x94C1-6alkyl)C(S)xe2x80x94;
M is selected from xe2x80x94Oxe2x80x94, xe2x80x94N(R12)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94C(O)N(R12)xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94N(R12)C(O)Oxe2x80x94, xe2x80x94OC(O)N(R12)xe2x80x94, xe2x80x94C(S)N(R12xe2x80x94, xe2x80x94N(R12)C(S)xe2x80x94, xe2x80x94SO2N(R12)xe2x80x94, xe2x80x94N(R12)SO2xe2x80x94 and xe2x80x94N(R12)C(O)N(R12)xe2x80x94, xe2x80x94N(R12)C(S)N(R12)xe2x80x94, xe2x80x94SO2NHC(O)xe2x80x94, xe2x80x94SO2N(R12)C(O)xe2x80x94, xe2x80x94C(O)NHSO2xe2x80x94, xe2x80x94C(O)N(R12)SO2xe2x80x94 or M is a direct bond;
D is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzoyl, (heterocyclic group)carbonyl, phenylsulphonyl, (heterocyclic group)sulphonyl, phenyl or a carbon linked heterocyclic group, and wherein any C1-6alkyl group may be optionally substituted by one or more R9, and wherein any phenyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R8 and if a heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from E;
E is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkanoyl, phenylC1-6alkyl, benzphenylhenylC1-6alkanoyl, phenylC1-6alkoxycarbonyl and phenylsulphonyl.
R9 is selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, formyl, sulphamoyl, Nxe2x80x94C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylamino, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl;
R10 is carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8;
R11 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an xe2x80x94NHxe2x80x94 moiety that nitrogen may be optionally substituted by a group selected from D, phenyl optionally substituted by one or more R8, C3-6cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8;
R12 is hydrogen or C1-6alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon attached to the nitrogen atom of M;
R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(Nxe2x80x94C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-64alkyl)2carbamoyl, C1-6alkoxycarbonyl, C1-6alkanoyl or formyl;
n is 0-2;
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Preferred values for R1, R2, R3, R4, R5, X and Yxe2x80x94Z are as follows
Preferably R1 and R2 are each independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C1-6alkyl substituted by a heterocyclic group, C1-6alkyl substituted by phenyl (which phenyl is optionally substituted by one or more substituents selected from halo, trifluoromethoxy, a heterocyclic group and trifluoromethyl), and phenyl which is optionally substituted by one or more substituents selected from halo, C1-4alkoxy, carbamoyl, trifluoromethyl, C1-4alkyl, nitro, hydroxy, cyano, C1-6alkanolyamino, C1-6alkylsulphonyl, C1-6alkanoyl and sulphamoyl,
or R1 and R2 together with the nitrogen group to which they are attached form morpholino or piperazine.
More preferably R1 and R2 are each independently selected from hydrogen, C1-5alkyl, C3alkenyl, C3-6cycloalkyl, pyridylCH2xe2x80x94, thienylCH2xe2x80x94, 1,3-benzodioxylCH2xe2x80x94, phenylCH2xe2x80x94 (which phenyl is optionally substituted by one or more substituents selected from fluoro, chloro, trifluoromethoxy, thiadiazole, and trifluoromethyl) and phenyl which is optionally substituted by one or more substituents selected from fluoro, chloro, bromo, iodo, methoxy, hydroxy, carbamoyl, C1-4alkyl, trifluoromethyl, nitro, cyano, sulphamoyl, C1-2alkanolyamino, mesyl and C1-2alkanoyl,
or R1 and R2 together with the nitrogen group to which they are attached form morpholino or piperazine.
Particularly R1 and R2 are each independently selected from hydrogen, methyl, ethyl, propenyl and phenyl which is substituted by one substituent selected from methoxy, chloro, iodo, hydroxy, carbamoyl, cyano, acetylamino, mesyl, acetyl and sulphamoyl,
or R1 and R2 together with the nitrogen group to which the are attached form morpholino.
More particularly R1 and R2 are each independently selected from hydrogen and phenyl which is substituted by one substituent selected from methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl and sulphamoyl.
Preferred combinations of R1 and R2 are as follows.
Preferably R1 and R2 are both methyl or ethyl, or one of R1 and R2 is methyl, ethyl or optionally substituted phenyl and the other is hydrogen, or R1 and R2 together with the nitrogen to which they are attached form morpholino.
More preferably one of R1 and R2 is hydrogen and the other is phenyl substituted with one substituent selected from methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl and sulphamoyl.
In another aspect of the invention, preferably R1 and R2 are each independently selected from
i) hydrogen;
ii) C1-6alkyl optionally substituted with one or more hydroxy, halo, C1-6alkoxy (optionally substituted with one or more hydroxy), C1-6alkoxycarbonyl, C1-6alkanoylamino, N,N-(C1-6alkyl)2amino, C1-6alkylsulphanyl, N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxycarbonyl), phenyl (optionally substituted with one or more halo, trifluoromethyl, C1-6alkoxy, C1-6alkyl, trifluoromethoxy, thiadiazolyl or sulphamoyl), pyridyl, thienyl, 1,3-benzodioxolyl, morpholino, piperidinyl, tetrahydrofuran and imidazolyl;
iii) phenyl optionally substituted with one or more halo, trifluoromethyl, nitro, cyano, hydroxy, sulphamoyl, carbamoyl, amino, formyl, carboxy, C1-4alkyl (optionally substituted with one or more hydroxy), C1-4alkoxy (optionally substituted with one or more phenyl), C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, C1-6alkylsulphanyl (optionally substituted with one or more hydroxy or C1-6alkoxy), C1-6alkylsulphonyl (optionally substituted with one or more hydroxy or C1-6alkoxy), N-(C1-6alkyl)amino (optionally substituted with one or more hydroxy), N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxy, N,N-(C1-6alkyl)2amino, hydroxy or tetrahydrofuran), N,N-(C1-6alkyl)2carbamoyl (optionally substituted with one or more hydroxy or C1-6alkoxy), N-(C2-6alkenyl)carbamoyl, N-(C3-6cycloalkyl)carbamoyl (optionally substituted with one or more hydroxy), N-(C2-6alkenyl)aminosulphonyl, N-(C3-6cycloalkyl)aminosulphonyl (optionally substituted with one or more hydroxy), N-(C1-6alkyl)aminosulphonyl (optionally substituted with one or more hydroxy, amino or N,N-(C1-6alkyl)2amino), N,N-(C1-6alkyl)2aminosulphonyl (optionally substituted with one or more hydroxy), C1-6alkanoylaminosulphonyl, C1-6alkylsulphonylaminocarbonyl, morpholinosulphonyl, piperazinylcarbonyl (optionally substituted on a ring nitrogen by C1-6alkyl), morpholinocarbonyl, pyrrolidinylsulphonyl (optionally substituted with one or more hydroxy);
iv) C3-6cycloalkyl (optionally substituted with one or more hydroxy);
v) C2-6alkenyl,
vi) C1-6alkanoyl [optionally substituted with one or more amino or phenyl (wherein said phenyl is optionally substituted with one or more halo)];
vii) benzoyl (optionally substituted with one or more halo, C1-6alkylsulphanyl, C1-6alkylsulphonyl, cyano, benzyloxy, C1-6alkoxy, trifluoromethyl, N,N-(C1-6alkyl)2aminosulphonyl, hydroxy);
viii) N-phenylcarbamoyl; or
ix) a heterocyclic group selected from tetrahydrofuran, piperidinyl (optionally substituted on a ring nitrogen with C1-6alkyl), pyridyl (optionally substituted with one or more trifluoromethyl, C1-6alkyl or halo), pyrimidinyl (optionally substituted with one or more C1-6alkyl or N,N-(C1-6alkyl)2amino), thienyl (optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C1-6alkyl) and pyrazinyl (optionally substituted with one or more C1-6alkyl);
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, piperidinyl [optionally substituted with one or more hydroxy, C1-6alkyl (wherein said C1-6alkyl is optionally substituted with hydroxy) or pyrrolidinyl], piperazinyl [optionally substituted on a ring nitrogen by C1-6alkoxycarbonyl, C1-6alkanoyl (wherein said C1-6alkanoyl is optionally substituted with one or more C1-6alkoxy, C1-6alkanoylamino, hydroxy or amino), C1-6alkyl (wherein said C1-6alkyl is optionally substituted with one or more hydroxy), C1-6alkylsulphonyl, phenylsulphonyl (wherein said phenylsulphonyl is optionally substituted with one or more C1-6alkylsulphonyl) morpholinocarbonyl or tetrahydrofurylcarbonyl], indolinyl, pyrrolyl, thiazolidinyl, pyrrolidinyl (optionally substituted with one or more hydroxy), thiomorpholino, 3-pyrrolinyl or homopiperazinyl (optionally substituted on a ring nitrogen with C1-6alkyl).
More preferably R1 and R2 are each independently selected from:
i) hydrogen;
ii) C1-6alkyl optionally substituted with one or more hydroxy, halo, C1-6alkoxy (optionally substituted with one or more hydroxy), C1-6alkoxycarbonyl, N,N-(C1-6alkyl)2amino, C1-6alkylsulphanyl, N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxycarbonyl), phenyl (optionally substituted with one or more halo or sulphamoyl), pyridyl, thienyl, 1,3-benzodioxolyl, morpholino, piperidinyl, tetrahydrofuran and imidazolyl;
iii) phenyl optionally substituted with one or more halo, trifluoromethyl, nitro, cyano, hydroxy, sulphamoyl, carbamoyl, amino, formyl, carboxy, C1-4alkyl (optionally substituted with one or more hydroxy), C1-4alkoxy (optionally substituted with one or more phenyl), C1-6alkanoyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, C1-6alkylsulphanyl (optionally substituted with one or more hydroxy or C1-6alkoxy), C1-6alkylsulphonyl (optionally substituted with one or more hydroxy or C1-6alkoxy), N-(C1-6alkyl)amino (optionally substituted with one or more hydroxy), N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxy, N,N-(C1-6alkyl)2amino, hydroxy or tetrahydrofuran), N,N-(C1-6alkyl)2carbamoyl (optionally substituted with one or more hydroxy or C1-6alkoxy), N-(C2-6alkenyl)carbamoyl, N-(C34cycloalkyl)carbamoyl (optionally substituted with one or more hydroxy), N-(C2-6alkenyl)aminosulphonyl, N-(C3-6cycloalkyl)aminosulphonyl (optionally substituted with one or more hydroxy), N-(C1-6alkyl)aminosulphonyl (optionally substituted with one or more hydroxy, or N,N-(C1-6alkyl)2amino), N,N-(C1-6alkyl)2aminosulphonyl (optionally substituted with one or more hydroxy), C1-6alkanoylaminosulphonyl, C1-6alkylsulphonylaminocarbonyl, morpholinosulphonyl, piperazinylcarbonyl (optionally substituted on a ring nitrogen by C1-6alkyl), morpholinocarbonyl, pyrrolidinylsulphonyl (optionally substituted with one or more hydroxy);
iv) C3-6cycloalkyl (optionally substituted with one or more hydroxy);
v) C2-6alkenyl,
vi) C1-6alkanoyl [optionally substituted with one or more phenyl (wherein said phenyl is optionally substituted with one or more halo)];
vii) benzoyl (optionally substituted with one or more halo, C1-6alkylsulphanyl, C1-6alkylsulphonyl, cyano, C1-6alkoxy, trifluoromethyl, N,N-(C1-6alkyl)2aminosulphonyl, hydroxy);
viii) a heterocyclic group selected from tetrahydrofuran, pyridyl (optionally substituted with one or more trifluoromethyl, C1-6alkyl or halo), pyrimidinyl (optionally substituted with one or more C1-6alkyl or N,N-(C1-6alkyl)2amino), thienyl (optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C1-6alkyl) and pyrazinyl (optionally substituted with one or more C1-6alkyl);
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, piperidinyl [optionally substituted with one or more hydroxy, C1-6alkyl (wherein said C1-6alkyl is optionally substituted with hydroxy) or pyrrolidinyl], piperazinyl [optionally substituted on a ring nitrogen by C1-6alkoxycarbonyl, C1-6alkanoyl (wherein said C1-6alkanoyl is optionally substituted with one or more C1-6alkoxy, C1-6alkanoylamino, hydroxy or amino), C1-6alkyl (wherein said C1-6alkyl is optionally substituted with one or more hydroxy), C1-6alkylsulphonyl, phenylsulphonyl (wherein said phenylsulphonyl is optionally substituted with one or more C1-6alkylsulphonyl) or morpholinocarbonyl], indolinyl, thiazolidinyl, pyrrolidinyl (optionally substituted with one or more hydroxy), thiomorpholino or 3-pyrrolinyl.
Particularly R1 and R2 are each independently selected from:
i) hydrogen;
ii) C1-6alkyl optionally substituted with one or more hydroxy, C1-6alkoxy, C1-6alkoxycarbonyl, C1-6alkylsulphanyl, N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxycarbonyl), phenyl (optionally substituted with one or more sulphamoyl), morpholino and tetrahydrofuran;
iii) phenyl optionally substituted with one or more halo, trifluoromethyl, hydroxy, sulphamoyl, amino, C1-4alkyl, C1-4alkoxy, C1-6alkoxycarbonyl, C1-6alkylsulphanyl (optionally substituted with one or more hydroxy or C1-6alkoxy), C1-6alkylsulphonyl (optionally substituted with one or more hydroxy or C1-6alkoxy), N-(C1-6alkyl)amino (optionally substituted with one or more hydroxy), N-(C1-6alkyl)carbamoyl (optionally substituted with one or more C1-6alkoxy, hydroxy or tetrahydrofuran), N,N-(C1-6alkyl)2carbamoyl (optionally substituted with one or more hydroxy), N-(C2-6alkenyl)carbamoyl, N-(C2-6alkenyl)aminosulphonyl, N-(C1-6alkenyl)aminosulphonyl (optionally substituted with one or more hydroxy or N,N-(C1-6alkyl)2amino), N,N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylaminocarbonyl, morpholinosulphonyl, pyrrolidinylsulphonyl (optionally substituted with one or more hydroxy);
iv) C3-6cycloalkyl (optionally substituted with one or more hydroxy);
v) C2-6alkenyl,
vi) C1-6alkanoyl [optionally substituted with one or more phenyl
vii) benzoyl (optionally substituted with one or more halo, cyano, C1-6alkoxy, hydroxy);
viii) a heterocyclic group selected from pyridyl (optionally substituted with one or more trifluoromethyl, C1-6alkyl or halo), pyrimidinyl (optionally substituted with one or more C1-6alkyl or N,N-(C1-6alkyl)2amino), thienyl (optionally substituted with one or more carbamoyl), isoxazolyl (optionally substituted with one or more C1-6alkyl) and pyrazinyl (optionally substituted with one or more C1-6alkyl);
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, piperidinyl [optionally substituted with one or more hydroxy or C1-6alkyl (wherein said C1-6alkyl is optionally substituted with hydroxy)], piperazinyl [optionally substituted on a ring nitrogen by C1-6alkoxycarbonyl, C1-6alkanoyl (wherein said C1-6alkanoyl is optionally substituted with one or more C1-6alkoxy, C1-6alkanoylamino, hydroxy or amino), C1-6alkylsulphonyl or morpholinocarbonyl], indolinyl or 3-pyrrolinyl.
More particularly R1 and R2 are each independently selected from hydrogen, methyl, cyclopropyl, 4-hydroxycyclohexyl, 2-hydroxyethyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 4-(morpholinosulphonyl)phenyl, pyrid-3-yl, 2-carbamoylthien-3-yl, 2-chloropyrid-3-yl, 5-chloropyrid-2-yl, 5-methylpyrid-2-yl, pyrimid-2-yl, 4,6-dimethylpyrimid-2-yl or 5,6-dimethylpyrazin-2-yl;
or R1 and R2 together with the nitrogen atom to which they are attached form 4-hydroxypiperidinyl or 1-(hydroxyacetyl)piperazin-4-yl.
In a further aspect of the invention, preferably R1 and R2 are independently selected from
i) hydrogen;
ii) C1-6alkyl or C3-6cycloalkyl optionally substituted with one or more C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or Nxe2x80x94(C1-6alkyl)2aminosulphonyl;
iii) a heterocyclic group selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, wherein said heterocyclic group is optionally substituted with one or more C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C1-6alkyl)2aminosulphonyl;
or R1 and R2 together with the nitrogen atom to which they are attached form piperidinyl or piperazinyl; wherein said piperidinyl and piperazinyl may be optionally substituted on a ring carbon by one or more groups selected from C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C1-6alkyl)2aminosulphonyl; and said piperazinyl may be optionally substituted on the ring nitrogen by a group selected from C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl and N,N-(C1-6alkyl)2carbamoyl; and wherein any C1-6alkyl group may be optionally substituted by one or more groups selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, Nxe2x80x94C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylamino, C1-6alkanoylamino, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl.
Preferably the R1R2NSO2xe2x80x94 group is para to Yxe2x80x94Z.
In one aspect of the invention R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3.
Preferably R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro, wherein k is 1-3,
or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
More preferably R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 fluorine atoms, wherein k is 1-2,
or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
Particularly R3 and R4 are independently methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl,
or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
More particularly R3 and R4 are independently methyl, fluoromethyl, difluoromethyl and trifluoromethyl,
or R3 and R4, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted by from 1 to 4 fluorine atoms.
Preferred combinations of R3 and R4 are as follows.
Preferably R3 and R4 are both methyl or one of R3 and R4 is methyl and the other is trifluoromethyl.
More preferably one of R3 and R4 is methyl and the other is trifluoromethyl.
Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (I).
Preferably R1 is ortho to Yxe2x80x94Z.
Preferably R5 is selected from halo, nitro, C1-4alkyl, C1-4alkoxy, hydroxy, hydrogen, amino, carboxy and sulphamoyl.
More preferably R5 is selected from fluoro, chloro, bromo, nitro, methyl, ethyl, methoxy, ethoxy, hydroxy, hydrogen, amino, carboxy and sulphamoyl.
Particularly R5 is selected from fluoro, chloro, nitro and methyl.
More particularly R5 is selected from fluoro and chloro.
Particularly preferred R5 is chloro ortho to Yxe2x80x94Z.
In another aspect of the invention preferably R5 is selected from halo, nitro, C1-4alkyl, C1-4alkoxy, C2-4alkenyl, C2-4alkynyl, hydroxy, hydrogen, amino, carboxy and sulphamoyl.
More preferably R5 is selected from fluoro, chloro, bromo, nitro, methyl, ethyl, methoxy, ethoxy, ethenyl, ethynyl, hydroxy, hydrogen, amino, carboxy and sulpharmoyl.
Particularly R5 is selected from fluoro, chloro, nitro, methyl, ethenyl and ethynyl.
Preferably X is phenyl.
Preferably Yxe2x80x94Z is selected from xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHC(S)xe2x80x94, trans-vinylene and ethynylene.
More preferably Yxe2x80x94Z is selected from xe2x80x94NHC(O)xe2x80x94 and xe2x80x94NHC(S)xe2x80x94.
Particularly Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94.
In a particular embodiment of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof (as herein before defined). Particular and preferred values are those mentioned above.
According to another aspect of the present invention there is provided a compound of the formula (Ia) 
wherein
R1a and R2a are independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C3-6Cycloalkyl, C1-6alkyl substituted by a heterocyclic group, C1-6alkyl substituted by phenyl (which phenyl is optionally substituted by one or more halo, trifluoromethoxy, a heterocyclic group or trifluoromethyl) and phenyl which is optionally substituted by one or more halo, C1-4alkoxy, carbamoyl, trifluoromethyl, C1-4alkyl, nitro, hydroxy, cyano, C1-6alkanolyamino, C1-6alkylsulphonyl, C1-6alkanoyl or sulphamoyl,
or R1a and R2a together with the nitrogen group to which the are attached form morpholino or piperazine;
R3a and R4a are independently methyl optionally substituted by from 1-3 fluoro;
R5a is selected from halo, nitro, C1-6alkyl, C1-6alkoxy, hydroxy, hydrogen, amino, carboxy and sulphamoyl;
G is O or S.;
with the proviso that where R1a and R2a are selected from hydrogen, C1-3alkyl or phenyl (which phenyl is optionally substituted by one or two substituents selected from halo, C1-4alkoxy, C1-4alkyl, hydroxy or cyano), R5a is nitro, C1-4alkyl, C1-4alkoxy or hydrogen and R3a and R4a are not both methyl, G must be S;
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (Ia).
A further preferred class of compounds is that of formula (Ib): 
wherein
R1b and R2b are independently selected from hydrogen, methyl, ethyl, C3alkenyl or phenyl which is substituted by one of methoxy, chloro, iodo, hydroxy, carbamoyl, cyano, acetylamino, mesyl, acetyl or sulphamoyl,
or R1b and R2b together with the nitrogen group to which the are attached form morpholino.
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
In a further aspect of the invention there is provided a compound of formula (Ib) wherein R1b and R2b are independently selected from:
i) hydrogen;
ii) C1-6alkyl or C3-6cycloalkyl optionally substituted with one or more C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C1-6alkyl)2aminosulphonyl;
iii) a heterocyclic group selected from pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, wherein said heterocyclic group is optionally substituted with one or more C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C1-6alkyl)2aminosulphonyl;
or R1b and R2b together with the nitrogen atom to which they are attached form piperidinyl or piperazinyl; wherein said piperidinyl and piperazinyl may be optionally substituted on a ring carbon by one or more groups selected from C1-6alkyl, C1-6alkoxy, C2-6alkenyloxy, hydroxy, halo, cyano, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulpharmoyl, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(Nxe2x80x94C1-6alkyl)amino, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, N-(C1-4alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl or N-(C1-6alkyl)2aminosulphonyl; and said piperazinyl may be optionally substituted on the ring nitrogen by a group selected from C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl and N,N-(C1-6alkyl)2carbamoyl; and wherein any C1-6alkyl group may be optionally substituted by one or more groups selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, Nxe2x80x94C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylamino, C1-6alkanoylamino, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl.
and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (Ib).
A further preferred class of compounds is that of formula (Ic): 
wherein:
K is methoxy, hydroxy, carbamoyl, cyano, acetyl, mesyl, or sulphamoyl, and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Where applicable, the R-configuration generally represents a preferred stereochemistry for compounds of formula (Ic).
Preferred compounds having formula (I) are Examples 1-37, 61-94 and 270 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Most preferred compounds having formula (I) are Examples 17, 34, 35, 36, 62, 78, 81 and 270 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
In another aspect of the invention, preferred compounds of the invention are any one of Examples 1-272 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
In a further aspect of the invention preferred compounds of the invention are Examples 27,43,44, 123, 143, 144, 145, 150, 166, 251, 252, 253, 255, 258, 259, 263 and 261 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
In an additional aspect of the invention preferred compounds of the invention are Examples 143, 145,251, 252 and 258 and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof.
Preferred aspects of the invention are those which relate to the compound or a pharmaceutically acceptable salt thereof.
Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which elevates PDH activity and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein.
It will be appreciated by those skilled in the art that certain compounds of formula (I) contain one or more asymmetrically substituted carbon and/or sulphur atoms, and accordingly may exist in, and be isolated as enantiomerically pure, a mixture of diastereoisomers or as a racemate-. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, enantiomerically pure, mixture of diastereoisomers, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the elevation of PDH activity, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallisation techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, (for example WO 9738124), by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the elevation of PDH activity by the standard tests described hereinafter.
It is also to be understood that certain compounds of the formula (I) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which elevate PDH activity.
A compound of the formula (I), or salt thereof, and other compounds of the invention (as hereinafter defined) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes include, for example, those illustrated in European Patent Applications, Publication Nos. 0524781, 0617010, 0625516, and in GB 2278054, WO 9323358 and WO 9738124.
Another aspect of the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, which process (in which variable groups are as defined for formula (I) unless otherwise stated) comprises of:
(a) deprotecting a protected compound of formula (II) 
where Pg is an alcohol protecting group;
(b) for a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94, by coupling an aniline of formula (III): 
with an acid of formula (IV): 
wherein G is a hydroxyl group;
(c) by coupling an aniline of formula (III) with an activated acid derivative of formula (IV) wherein G is a hydroxyl group which may be protected as an ester or ether;
(d) for a compound of formula (I) in which Yxe2x80x94Z is ethynylene, by reacting a alkyne of formula (V): 
with a base, followed by treatment with a ketone of formula (VI): 
(e) for a compound of formula (I) in which Yxe2x80x94Z is trans-vinylene, by reducing a compound of formula (I) in which Yxe2x80x94Z is ethynylene;
(f) for a compound of formula (I) in which Yxe2x80x94Z is trans-vinylene, by dehydration of a diol of formula (VII): 
(g) for a compound of formula (I) in which Yxe2x80x94Z is trans-vinylene, by base catalysed opening of an epoxide of formula (VIII): 
(h) for a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHCH2xe2x80x94, by reducing a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94;
(i) for a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94OCH2xe2x80x94, xe2x80x94SCH2xe2x80x94 or xe2x80x94NHCH2xe2x80x94 by reacting an ethylene oxide of formula (IX): 
with a compound of formula (III) or a compound of formula (X): 
where J is xe2x80x94OH, xe2x80x94NH2 or xe2x80x94SH;
(j) by reacting a compound of formula (XI): 
where K is a leaving atom or group, and in which Yxe2x80x94Z is OCH2, SCH2 or NHCH2 or xe2x80x94NHC(O)xe2x80x94 with an amine of formula R1R2NH;
(k) for a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(S)xe2x80x94, by reacting a compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94 with a sulphur reagent; and thereafter if necessary:
i) converting a compound of the formula (I) into another compound of the formula (I);
ii) removing any protecting groups; or
iii) forming a pharmaceutically acceptable salt or in vivo hydrolysable ester.
Suitable values for Pg are a benzyl group, a silyl group or an acetyl protecting group.
K is a leaving atom or group, suitable values for K are for example a halogen atom such as fluoro or chloro.
Specific conditions of the above reactions are as follows:
a) Suitable reagents for deprotecting an alcohol of formula (II) are for example:
1) when Pg is benzyl:
(i) hydrogen in the presence of palladium/carbon catalyst, i.e. hydrogenolysis; or
(ii) hydrogen bromide or hydrogen iodide;
2) when Pg is a silyl protecting group:
(i) tetrabutylammonium fluoride; or
(ii) aqueous hydrofluoric acid;
3) when Pg is acetyl:
i) mild aqueous base for example lithium hydroxide.
The reaction can be conducted in a suitable solvent such as ethanol, methanol, acetonitrile, or dimethylsulphoxide and may conveniently be performed at a temperature in the range of xe2x88x9240 to 100xc2x0 C.
(b) An aniline of formula (III) and an acid of formula (IV) may be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, for example thionyl chloride (or oxalyl chloride), carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.
(c) An aniline of formula (III) may be coupled with an activated acid derivative of formula (IV) for example acid chlorides, acid anhydrides, or phenyl esters, wherein G is a hydroxyl group which may be suitably protected as a stable ester or ether. This coupling may be achieved optionally in the presence of a base for example triethyl amine, pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran, and dimethylformamide. The coupling reaction may conveniently be performed at a temperature in the range of xe2x88x9240 to 40xc2x0 C.;
(d) suitable bases for reacting with a corresponding alkyne of formula (V) are for example lithium diisopropylamide (LDA), n-butyllithium or tert-butyllithium. The reaction with a ketone of formula (IV) may be performed at a temperature in the range of xe2x88x92100 to xe2x88x9240xc2x0 C. preferably at a temperature in the range of xe2x88x9270 to xe2x88x9240xc2x0 C. and in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane.
(e) A suitable reducing agent for a compound of formula (I) in which Yxe2x80x94Z is trans-vinylene is, for example, lithium aluminium hydride or sodium bis(methoxyethoxy)aluminium hydride. The reaction can be conducted in a suitable solvent such as tetrahydrofuran or diethyl ether, and at a temperature in the range of 0 to 50xc2x0 C.
(f) Dehydration of a diol of formula (VII) may be conducted in the presence of an acid catalyst (for example p-toluenesulphonic acid), neat or with a solvent such as toluene or dichloromethane at a temperature in the range of 0 to 200xc2x0 C. preferably a temperature in the range of 20 to 100xc2x0 C.
(g) Base catalysed opening of an epoxide of formula (VIII) may be carried out in a suitable organic solvent for example, ethers or toluene. Ethers such as tetrahydrofuran are preferred. Suitable bases include potassium tert-butoxide or sodium hydride. The opening may be carried out at a temperature in the range of xe2x88x9250 to 100xc2x0 C., preferably at a temperature in the range of 0 to 50xc2x0 C. for example room temperature.
(h) A compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94 may be reduced with a suitable reducing agent such as lithium aluminium hydride or borane. The reaction can conveniently be carried out at a temperature in the range of 0xc2x0 C. to reflux, in solvents such as for example diethyl ether, tetrahydrofuran, or 1,2-dimethoxyethane.
(i) An ethylene oxide of formula (IX) may be reacted with a corresponding compound of formula (III) or a compound of formula (X) in the presence of a base for example sodium hydride or triethylamine. The reaction can be conducted at reflux in a solvent such as dichloromethane, tetrahydrofuran, or diethyl ether.
(j) A compound of formula (XI) where K is a leaving atom or group, for example a halogen atom such as fluoro or chloro and in which Yxe2x80x94Z is OCH2, SCH2 or NHCH2 or xe2x80x94NHC(O)xe2x80x94 may be reacted with an amine of formula R1R2NH in the presence of a base, for example a tertiary amine such as triethylamine and in the presence of a catalyst for example dimethylaminopyridine. Suitable solvents for the reaction include nitriles such as acetonitrile and amides such as dimethylformamide. The reaction is conveniently performed at a temperature in the range of from 0 to 120xc2x0 C.
(k) A compound of formula (I) in which Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94 may be reacted with a reagent such as for example phosphorus pentasulphide or Lawesson""s reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide), optionally in the presence of a suitable base such as for example pyridine or triethylamine. Suitable solvents for the reaction include for example toluene, tetrahydrofuran, 1,3-dioxane or acetonitrile. The reaction is conveniently performed at a temperature in the range of from 0 to reflux.
If not commercially available, the necessary starting materials for the procedures such as that described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples.
For example, it will be appreciated that certain of the optional aromatic substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acylhalide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl using, for example, hydrogen peroxide in acetic acid with heating or 3-chloroperbenzoic acid.
Specific examples of the techniques used to make that starting materials described above are illustrated, but not limited by, the following examples in which variable groups are as defined for formula (I) unless otherwise stated.
a) compounds of formula (II) in which Yxe2x80x94Z is OCH2, SCH2 or NHCH2 may be made by treating the corresponding compound of formula (X) wherein J is xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2 or a compound of formula (III) with a compound of formula (XII): 
where Y is a leaving group for example mesylate; in the presence of a base such as an alkali metal hydride (e.g. sodium hydride), in a solvent such as tetrahydrofuran,
N,N-dimethylformamide, dimethyl sulphoxide, or
1,3-Dimethyl-3,4,5,6tetrahydro-2(1H)pyrimidinone, and at a temperature of 20xc2x0 C. to reflux.
b) A compound of formula (II), wherein Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94, may be made by coupling a compound of formula (III) with a compound of formula (IV) (where G is hydroxy protected with a protecting group) in a manner analogous to that described for procedure (b) of preparations of a compound of formula (I) above.
Compounds of formula (IV) where G is hydroxy protected with a protecting group may be made by conventional procedures. For example, cleavage of the ester group of a compound of formula (XII): 
where E is a carboxy protecting group (e.g. Me);
under standard conditions such as mild alkaline conditions, for example, aqueous lithium hydroxide.
Compounds of formula (XIII) where G is protected hydroxy are prepared by protecting a compound of formula (XIII) where G is hydroxy by reaction with a compound such as benzyl chloride or benzyl bromide (in the presence of a suitable base such as sodium hydride and optionally with a catalyst such as sodium iodide, to provide a benzyl protecting group) or any of the conventional silylating agents known and used for such purpose (for example 2-trimethylsilylethoxymethyl chloride, in the presence of a suitable base such as triethylamine optionally in the presence of a catalyst such as dimethylaminopyridine).
Compounds of formula (XIII) where G is hydroxy are prepared by esterifying an acid of formula (IV) by a conventional esterification procedure such as reaction with a C1-6alcohol (e.g. methanol) in the presence of an acid catalyst (for example sulphuric acid).
c) A compound of formula (II), wherein Yxe2x80x94Z is ethynylene, may be made by reacting a compound of formula (XIV): 
wherein L is a leaving group such as bromo, iodo, or triflate, with an acetylene of formula (XV) 
in the presence of a catalyst such as a combination of copper (I) iodide and bis(triphenylphosphine)palladium dichloride or palladium (II) acetate. The reaction can be conducted in an inert solvent such as tetrahydrofuran, benzene, or toluene, or in a basic solvent such as diethylamine or triethylamine, and at a temperature in the range of xe2x88x9220 to 110xc2x0 C.
A compound of formula (XV) may be made by reacting a compound of formula (XVI) 
with an agent such as:
i) benzyl bromide (to provide a benzyl protecting group), this reaction may conveniently be conducted in the presence of a base such as sodium hydride and optionally in the presence of a catalyst such as sodium iodide in a solvent such as tetrahydrofuran at a temperature of about xe2x88x9278 to about 100xc2x0 C.; or
ii) any of the conventional silylating agents known and used for such purpose (such as for example tert-butyl dimethylsilylchloride or triflate, in the presence of a suitable base such as 1,8-Diazabicyclo[5.4.0]undec-7-ene or triethylamine optionally in the presence of a catalyst such as dimethylaminopyridine) at a temperature of about xe2x88x9278 to about 100xc2x0 C.
d) A compound of formula (II), wherein Yxe2x80x94Z is trans-vinylene, may be made by reacting a compound of formula (XVII): 
where M is an alkylmetal group such as a trialkyltin (for example tributyl- or trimethyl-tin) or a bisalkyloxyborane (for example catecholborane);
with a compound of formula (X), wherein J may be a leaving group for example iodide, bromide or triflate in the presence of a catalyst such as bis(triphenylphosphine)palladium dichloride or tetrakis(triphenylphosphine)palladium (0). The reaction may conveniently be conducted in a suitable inert solvent such as a tetrahydrofuran or dimethylformamide at a temperature of 0-150xc2x0 C.
A compound of formula (XVII) may be made by a reaction of a compound of formula (XV)
i) with an agent such as catecholborane, to form the vinylborane compound; or
ii) a trialkyltinhydride in the presence of a catalytic amount of a radical chain initiator such as, for example, aza-bis-isobutyronitrile or by using trialkyltinhydride pre-treated with a strong base (such as an alkyllithium) and copper (I) cyanide, or by using a transition metal catalyst such as, for example, tetrakis(triphenylphosphine)palladium(0) to form a compound of formula (XVII) where M is trialkyltin.
These reactions may conveniently be conducted in a suitable inert solvent such as tetrahydrofuran, toluene or xylene at a temperature of from 0-150xc2x0 C.
Compounds of formula (XVI) may be made by reacting a compound of formula (VI) with an alkali metal acetylide (for example lithium acetylide) or alkaline earth metal acetylide (for example magnesium acetylide). The reaction may be conducted in a solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane and at a temperature of xe2x88x92100 to 25xc2x0 C.
A compound of formula (III) may be prepared:
i) from a compound of formula (XVIII) 
wherein Pg is a protective group such as for example acetyl;
a) by treatment with chlorosulphonic acid under standard conditions, and then
b) formation of the sulphonamide under standard conditions as described above in process (j) for preparation of a compound of formula (I) and then
c) cleavage of the protecting group under mild alkaline conditions (for example when Pg is acetyl with a base such as aqueous sodium hydroxide); or
ii) by reducing a compound of formula (XIX): 
under standard conditions for example by a reducing agent such as tin (II) chloride or iron dust in conjunction with concentrated acid to give a compound of formula (III).
A compound of formula (XIX) may be made by reacting a compound of formula (XX): 
with an amine of formula R1R2NHxe2x80x94 in a procedure analogous to that used in process (j) for preparation of a compound of formula (I) above.
A compound of formula (XX) may be prepared:
a) by oxidising a compound of formula (XXI): 
under standard conditions for example with chlorine in a suitable solvent such as acetic acid at a temperature of xe2x88x9278 to about 100xc2x0 C.; or
b) by diazotizing a compound of formula (XXII): 
under standard conditions for example with nitrous acid and sulphuric acid followed by reaction with a mixture of sulphur dioxide and copper (II) chloride in a suitable solvent such as water or a water/acetic acid solution.
If the resolved acid is required it may be prepared by any of the known methods for preparation of optically-active forms (for example, by recrystallisation of the chiral salt {for example WO 9738124}, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase). For example if an (R)-(+) resolved acid is required it may be prepared by the method of Scheme 2 in World Patent Application Publication No. WO 9738124 for preparation of the (S)-(xe2x88x92) acid, i.e. using the classical resolution method described in European Patent Application Publication No. EP 0524781, also for preparation of the (S)-(xe2x88x92) acid, except that (1S,2R)-norephedrine may be used in place of (S)-(xe2x88x92)-1-phenylethylamine.
A compound of formula (V) may be prepared by reacting a compound of formula (XIV), wherein L is bromo, iodo or triflate with trimethylsilylacetylene in the presence of a catalyst such as a combination of bis(triphenylphosphine)palladium dichloride and copper(I) iodide in diethylamine or triethylamine, followed by treatment with a base (for example potassium carbonate) in a C1-6alcohol (such as methanol) as the solvent to remove the trimethylsilyl group.
A compound of formula (VII) may be prepared from a compound of formula (XXIII): 
by reduction under standard conditions for example by using a hydride, such as sodium borohydride.
A compound of formula (XXIII) may be prepared by deprotonation of a compound of formula (XXIV), 
with a strong base, for example lithium diisopropyl amide in an organic solvent, for example tetrahydrofuran at a temperature of xe2x88x9278 to 100xc2x0 C. followed by addition of an amide of formula (XXV): 
in which R19 and R20 are each independently C1-6alkyl or together with the atoms to which they are attached form a 5-7 membered ring.
An amide of formula (XXV) may be prepared from an acid of formula (IV), or a reactive derivative thereof, by reaction with an amine of formula R19(R20O)NH under standard conditions such as those described in process (b) for preparation of a compound of formula (I) above.
A compound of formula (VIII) may be prepared from a diol of formula (VII) using a suitable dehydrating agent, for example bis[xcex1,xcex1-bis(trifluoromethyl)benzenemethanolato]diphenyl sulphur.
A compound of formula (IX) may be made by treating a compound of formula (VI) with a trimethylsulphonium salt (such as trimethylsulphonium iodide) and a base (such as an alkali metal hydroxide) in a solvent such as dichloromethane.
a) A compound of formula (X) wherein J is xe2x80x94OH, may be prepared by diazotizing a compound of formula (III) under standard conditions such as those described above in 2(ii) above followed by heating the resulting compound in dilute sulphuric acid.
b) A compound of formula (X), wherein J is xe2x80x94SH, may be prepared by reacting a compound of formula (XIV) where L is a leaving group (for example chloro) with an excess of methanethiol in the presence of sodium hydride.
A compound of formula (XI) wherein K is chloro, in which Yxe2x80x94Z is OCH2, SCH2, NHCH2 or xe2x80x94NHC(O)xe2x80x94 may be prepared by
1) either
a) coupling a compound of formula (XXVI) 
wherein J is xe2x80x94OH, xe2x80x94SH or NH2 with a compound of formula (XII) where Y is a leaving group for example mesylate; in the presence of a base such as an alkali metal hydride (e.g. sodium hydride), in a solvent such as tetrahydrofuran, N,N-dimethylformamide, dimethyl sulphoxide, or
1,3-Dimethyl-3,4,5,6tetrahydro-2(1H)-pyrimidinone, and at a temperature of 20xc2x0 C. to reflux; or
b) where Yxe2x80x94Z is xe2x80x94NHC(O)xe2x80x94 coupling with a compound of formula (XXVI) where J is NH2 with a compound of formula (IV), following a method analogous to that of process (b) for preparation of a compound of formula (I) above.
Route a or b is then followed by:
2) treatment with chlorosulphonic acid.
A compound of formula (XII), wherein Y is mesylate may be prepared by reacting a compound of formula (XXVII): 
with methanesulphonicacid chloride in the presence of a base such as triethylamine, in a solvent such as dichloromethane, and at a temperature of about xe2x88x9278 to 25xc2x0 C.
Compounds of formula (XXVII) are prepared by reducing a compound of formula (XIII) with a suitable reducing agent such as lithium aluminium hydride in a solvent such as diethyl ether or THF and at a temperature of about 0 to about 25xc2x0 C.
It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
In cases where compounds of formula (I) are sufficiently basic or acidic to form stable acid or basic salts, administration of the compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described following. Examples of suitable pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methanesulphonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, xcex1-ketoglutarate, and xcex1-glycerophosphate. Suitable inorganic salts may also be formed such as sulphate, nitrate, and hydrochloride.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound of formula (I) (or its ester) with a suitable acid affording a physiologically acceptable anion. It is also possible with most compounds of the invention to make a corresponding alkali metal (e.g. sodium, potassium, or lithium) or alkaline earth metal (e.g. calcium) salt by treating a compound of formula (I) (and in some cases the ester) with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g. the ethoxide or methoxide) in aqueous medium followed by conventional purification techniques.
In vivo cleavable esters of compounds of the invention may be made by coupling with a pharmaceutically acceptable carboxylic acid or an activated derivative thereof. For example, the coupling may be carried out by treating a compound of formula (I) with an appropriate acid chloride (for example, acetyl chloride, propionyl chloride, or benzoyl chloride) or acid anhydride (for example, acetic anhydride, propionic anhydride, or benzoic anhydride) in the presence of a suitable base such as triethylamine. Those skilled in the art will appreciate that other suitable carboxylic acids (including their activated derivatives) for the formation of in vivo cleavable esters are known to the art and these are also intended to be included within the scope of the invention. Catalysts such as 4-dimethylaminopyridine may also be usefully employed.
Many of the intermediates defined herein are novel and these are provided as a further feature of the invention.
The identification of compounds which elevate PDH activity is the subject of the present invention. These properties may be assessed, for example, using one or more of the procedures set out below:
(a) In vitro Elevation of PDH Activity
This assay determines the ability of a test compound to elevate PDH activity. cDNA encoding PDH kinase may be obtained by Polymerase Chain Reaction (PCR) and subsequent cloning. This may be expressed in a suitable expression system to obtain polypeptide with PDH kinase activity. For example rat PDHkinaseII (rPDHKII) obtained by expression of recombinant protein in Escherichia coli (E. Coli), was found to display PDH kinase activity.
In the case of the rPDHKII (Genbank accession number U10357) a 1.3 kb fragment encoding the protein was isolated by PCR from rat liver cDNA and cloned into a vector (for example pQE32xe2x80x94Quiagen Ltd.). The recombinant construct was transformed into E. coli (for example M15pRep4xe2x80x94Quiagen Ltd.). Recombinant clones were identified, plasmid DNA was isolated and subjected to DNA sequence analysis. One clone which had the expected nucleic acid sequence was selected for the expression work. Details of the methods for the assembly of recombinant DNA molecules and the expression of recombinant proteins in bacterial systems can be found in standard texts for example Sambrook et al, 1989, Molecular Cloningxe2x80x94A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press. Other known PDH kinases for use in assays, may be cloned and expressed in a similar manner.
For expression of rPDHKII activity, E. coli strain M15pRep4 cells were transformed with the pQE32 vector containing rPDHKII cDNA. This vector incorporates a 6-His tag onto the protein at its N-terminus. E. coli were grown to an optical density of 0.6 (600 nM) and protein expression was induced by the addition of 10 xcexcM isopropylthio-xcex2-galactosidase. Cells were grown for 18 hours at 18xc2x0 C. and harvested by centrifugation. The resuspended cell paste was lysed by homogenisation and insoluble material removed by centrifugation at 24000xc3x97g for 1 hour. The 6-His tagged protein was removed from the supernatant using a nickel chelating nitrilotriacetic acid resin (Ni-NTA: Quiagen Ltd.) matrix (Quiagen) which was washed with 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 20 mM imidazole, 0.5 M sodium chloride pH 8.0, prior to elution of bound protein using a buffer containing 20 mM tris(hydroxymethyl)aminomethane-hydrogen chloride, 200 mM imidazole, 0.15 M sodium chloride pH 8.0. Eluted fractions containing 6-His protein were pooled and stored in aliquots at xe2x88x9280xc2x0 C. in 10% glycerol.
Each new batch of stock enzyme was titrated in the assay to determine a concentration giving approximately 90% inhibition of PDH in the conditions of the assay. For a typical batch, stock enzyme was diluted to 7.5 xcexcg/ml.
For assay of the activity of novel compounds, compounds were diluted with 10% dimethylsulphoxide (DMSO) and 10 xcexcl transferred to individual wells of 96-well assay plates. Control wells contained 20 xcexcl 10% DMSO instead of compound. 40 xcexcl Buffer containing 50 mM potassium phosphate buffer pH 7.0, 10 mM ethylene glycol-bis(xcex2-aminoethyl ether)-N,N,N,N-tetracetic acid (EGTA), 1 mM benzamidine, 1 mM phenylmethylsulphonyl fluoride (PMSF), 0.3 mM tosyl-L-lysine chloromethyl ketone (TLCK), 2 mM dithiothreitol (DTT), recombinant rPDHKII and compounds were incubated in the presence of PDH kinase at room temperature for 45 minutes. In order to determine the maximum rate of the PDH reaction a second series of control wells were included containing 10% DMSO instead of compound and omitting rPDHKII. PDH kinase activity was then initiated by the addition of 5 xcexcM ATP, 2 mM magnesium chloride and 0.04 U/ml PDH (porcine heart PDH Sigma P7032) in a total volume of 50 xcexcl and plates incubated at ambient temperature for a further 45 minutes. The residual activity of the PDH was then determined by the addition of substrates (2.5 mM coenzyme A, 2.5 mM thiamine pyrophosphate (cocarboxylase), 2.5 mM sodium pyruvate, 6 mM NAD in a total volume of 80 xcexcl and the plates incubated for 90 minutes at ambient temperature. The production of reduced NAD (NADH) was established by measured optical density at 340 nm using a plate reading spectrophotometer. The ED50 for a test compound was determined in the usual way using results from 12 concentrations of the compound.
(b) In vitro Elevation of PDH Activity in Isolated Primary Cells
This assay determines the ability of compounds to stimulate pyruvate oxidation in primary rat hepatocytes.
Hepatocytes were isolated by the two-step collagenase digestion procedure described by Seglen (Methods Cell Biol. (1976) 13, 29-33) and plated out in 6-well culture plates (Falcon Primaria) at 600000 viable cells per well in Dulbecco""s Modified Eagles Medium (DMEM, Gibco BRL) containing 10% foetal calf serum (FCS), 10% penicillin/streptomycin (Gibco BRL) and 10% non-essential amino acids (NEAA, Gibco BRL). After 4 hours incubation at 37xc2x0 C. in 5% CO2, the medium was replaced with Minimum Essential Medium (MEM, Gibco BRL) containing NEAA and penicillin/streptomycin as above in addition to 10 nM dexanethasone and 10 nM insulin.
The following day cells were washed with phosphate buffered saline (PBS) and medium replaced with 1 ml HEPES-buffered Krebs solution (25 mM HEPES, 0.1 SM sodium chloride, 25 mM sodium hydrogen carbonate, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium sulphate, 1 mM potassium dihydrogen phosphate) containing the compound to be tested at the required concentration in 0.1% DMSO. Control wells contained 0.1% DMSO only and a maximum response was determined using a 10 xcexcM treatment of a known active compound. After a preincubation period of 40 minutes at 37xc2x0 C. in 5% CO2, cells were pulsed with sodium pyruvate to a final concentration of 0.5 mM (containing 1-4C sodium pyruvate (Amersham product CFA85) 0.18 Ci/mmole) for 12 minutes. The medium was then removed and transferred to a tube which was immediately sealed with a bung containing a suspended centre well. Absorbent within the centre well was saturated with 50% phenylethylamine, and CO2 in the medium released by the addition of 0.2 xcexcl 60% (w/v) perchloric acid (PCA). Released 14CO2 trapped in the absorbent was determined by liquid scintillation counting. The ED50 for a test compound was determined in the usual way using results from 7 concentrations of the compound.
(c) In vivo Elevation of PDH Activity
The capacity of compounds to increase the activity of PDH in relevant tissues of rats may be measured using the test described hereinafter. Typically an increase in the proportion of PDH in its active, nonphosphorylated form may be detected in muscle, heart, liver and adipose tissue after a single administration of an active compound. This may be expected to lead to a decrease in blood glucose after repeated administration of the compound. For example a single administration of DCA, a compound known to activate PDH by inhibition of PDH kinase (Whitehouse, Cooper and Randle (1974) Biochem. J. 141, 761-774) 150 mg/kg, intraperitoneally, increased the proportion of PDH in its active form (Vary et al. (1988) Circ. Shock 24, 3-18) and after repeated administration resulted in a significant decrease in plasma glucose (Evans and Stacpoole (1982) Biochem. Pharmacol. 31, 1295-1300).
Groups of rats (weight range 140-180 g) are treated with a single dose or multiple doses of the compound of interest by oral gavage in an appropriate vehicle. A control group of rats is treated with vehicle only. At a fixed time after the final administration of compound, animals are terminally anaesthetised, tissues are removed and frozen in liquid nitrogen. For determination of PDH activity, muscle samples are disrupted under liquid nitrogen prior to homogenisation by one thirty-second burst in a Polytron homogenizer in 4 volumes of a buffer containing 40 mM potassium phosphate pH 7.0, 5 mM EDTA, 2 mM DTT, 1% Triton X-100, 10 mM sodium pyruvate, 10 xcexcM phenylmethylsulphonyl chloride (PMSF) and 2 xcexcg/ml each of leupeptin, pepstain A and aprotinin. Extracts are centrifuged before assay. A portion of the extract is treated with PDH phosphatase prepared from pig hearts by the method of Siess and Wieland (Eur. J. Biochem (1972) 26, 96): 20 xcexcl extract, 40 xcexcl phosphatase (1:20 dilution), in a final volume of 125 xcexcl containing 25 mM magnesium chloride, 1 mM calcium chloride. The activity of the untreated sample is compared with the activity of the dephosphorylated extract thus prepared PDH activity is assayed by the method of Stansbie et al., (Biochem. J. (1976) 154, 225). 50 xcexcl Extract is incubated with 0.75 mM NAD, 0.2 mM CoA, 1.5 mM thiamine pyrophosphate (TPP) and 1.5 mM sodium pyruvate in the presence of 20 xcexcg/ml p-(p-amino-phenylazo) benzene sulphonic acid (AABS) and 50 mU/ml arylamine transferase (AAT) in a buffer containing 100 mM tris(hydroxymethyl)aminomethane, 0.5 mM EDTA, 50 mM sodium fluoride, 5 mM 2-mercaptoethanol and 1 mM magnesium chloride pH 7.8. AAT is prepared from pigeon livers by the method of Tabor et al. (J. Biol. Chem. (1953) 204, 127). The rate of acetyl CoA formation is determined by the rate of reduction of AABS which is indicated by a decrease in optical density at 460 nm.
Liver samples are prepared by an essentially similar method, except that sodium pyruvate is excluded from the extraction buffer and added to the phosphatase incubation to a final concentration of 5 mM.
Treatment of an animal with an active compound results in an increase in the activity of PDH complex in tissues. This is indicated by an increase in the amount of active PDH (determined by the activity of untreated extract as a percentage of the total PDH activity in the same extract after treatment with phosphatase).
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) as defined hereinbefore or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable excipient or carrier.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I) which is selected from:
i) a compound of the formula (I) wherein R3 and R4 are both methyl, R5 is hydrogen, fluoro or chloro, Yxe2x80x94Z is ethynylene, X is phenyl and one of R1 and R2 is hydrogen and the other is pyrimidyl-NHxe2x80x94C(O)xe2x80x94 or triazinyl-NHxe2x80x94C(O)xe2x80x94 (wherein said triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) and the xe2x80x94SO2NR1R2 moiety is ortho to Yxe2x80x94Z;
ii) 4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide;
iii) N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; or
iv) N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable excipient or carrier.
The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository. In general the above compositions may be prepared in a conventional manner using conventional excipients.
The compositions of the present invention are advantageously presented in unit dosage form. The compound will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg. A unit dose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
According to a further aspect of the present invention there is provided a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that compounds of the present invention elevate PDH activity and are therefore of interest for their blood glucose-lowering effects.
A further feature of the present invention is a compound of formula (I) and pharmaceutically acceptable salts or in vivo hydrolysable esters thereof for use as a medicament.
Conveniently this is a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for use as a medicament for producing an elevation of PDH activity in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof in the manufacture of a medicament for use in the production of an elevation of PDH activity in a warm-blooded animal such as a human being.
According to a further feature of the invention there is provided a method for producing an elevation of PDH activity in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo-hydrolysable ester thereof as defined hereinbefore.
For the avoidance of doubt, in aspects of the invention concerning the use of compounds of formula (I) or pharmaceutically acceptable salts or in vivo hydrolysable esters thereof in medicine, the definition of compounds includes compounds selected from:
i) a compound of the formula (I) wherein R3 and R1 are both methyl, R5 is hydrogen, fluoro or chloro, Yxe2x80x94Z is ethynylene, X is phenyl and one of R1 and R2 is hydrogen and the other is pyrimidyl-NHxe2x80x94C(O)xe2x80x94 or triazinyl-NHxe2x80x94C(O)xe2x80x94 (wherein said triazine or pyrimidine is substituted by methyl, methoxy or dimethylamino) and the xe2x80x94SO2NR1R2 moiety is ortho to Yxe2x80x94Z;
ii) 4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide;
iii) N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide; or
iv) N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide;
and their pharmaceutically acceptable salts and in vivo hydrolysable esters.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
The elevation of PDH activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. For example in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment:
i) insulin;
ii) insulin secretagogue agents designed to stimulate insulin secretion (for example glibenclamide, tolbutamide, other sulphonylureas);
iii) oral hypoglycaemic agents such as metformin, thiazolidinediones;
iv) agents designed to reduce the absorption of glucose from the intestine (for example acarbose);
v) agents designed to treat complications of prolonged hyperglycaemia;
vi) other agents used to treat lactic acidaemia;
vii) inhibitors of fatty acid oxidation;
viii) lipid lowering agents;
ix) agents used to treat coronary heart disease and peripheral vascular disease such as aspirin, pentoxifylline, cilostazol; and/or
x) thiamine.
As stated above the compounds defined in the present invention are of interest for their ability to elevate the activity of PDH. Such compounds of the invention may therefore be useful in a range of disease states including diabetes mellitus, peripheral vascular disease, (including intermittent claudication), cardiac failure and certain cardiac myopathies, myocardial ischaemia, cerebral ischaemia and reperfusion, muscle weakness, hyperlipidaemias, Alzheimers disease and/or atherosclerosis.
In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of elevators of PDH activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (xc2x0 C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25xc2x0 C.;
(ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60xc2x0 C.;
(iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a xe2x80x9cBond Elutxe2x80x9d column is referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, Calif., USA under the name xe2x80x9cMega Bond Elut SIxe2x80x9d
(iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;
(v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vi) when given, 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-d6) as the solvent unless otherwise stated; coupling constants (J) are given in Hz;
(vii) chemical symbols have their usual meanings; SI units and symbols are used;
(viii) solvent ratios are given in percentage by volume;
(ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where indicated ionisation was effected by electron impact (EI) or fast atom bombardment (FAB); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the negative mass ion xe2x80x94(Mxe2x80x94H)xe2x80x94; and
(x) the following abbreviations are used: